This project was a prospective, placebo-controlled, randomized study to evaluate the effectiveness of 3,4-diaminopyridine (DAP) in patients with Lambert-Eaton myasthenic syndrome (LEMS), and to determine the common short and long term side-effects of DAP. (DAP is an orphan drug that has been used elsewhere in the world for over 20 years to improve strength in patients with LEMS, myasthenia gravis [MG], and congenital myasthenic syndromes. In many countries it is considered standard therapy for LEMS.) Twenty six patients with LEMS completed a 2-arm parallel treatment protocol in which DAP, 20 mg tid, or placebo was given blindly for 6 days, and a quantitative examination of muscle strength was used as the primary measure of efficacy. The last patient completed the blinded, in-patient protocol in May, 1998, and 3 months later the assignment code was broken. Twelve patients had received DAP and 14 had received placebo. There was no difference in the age of LEMS onset, gender distribution, incidence of lung cancer, or baseline muscle strength between the placebo and active drug groups. Analysis by 2-tailed t-test demonstrated that patients who had received DAP had a significantly greater improvement in the quantitative measure of neuromuscular function and in a physiologic measurement of muscle electrical response. There was also a significant improvement in a physician-applied assessment of muscle strength in limb muscles. After the blinded study, patients were given open-label DAP and monitored for side effects as long as there was symptomatic improvement. All but one LEMS patient had significant symptomatic improvement from subsequent open-label administration of DAP. Side-effects of DAP were negligible, consisting of perioral and digital paresthesias. Laboratory measurements demonstrated no evidence of toxicity affecting liver, renal, hematologic, endocrinologic, encephalographic or electrocardiologic function acutely or after 6 months of open-label DAP. This study corroborates previous studies and many years of clinical experience which suggest that DAP is an effective and safe treatment for most patients with LEMS and should be available for clinical use in this country.